Welcome to PracticeUpdate! We hope you are enjoying access to a selection of our top-read and most recent articles. Please register today for a free account and gain full access to all of our expert-selected content.
Already Have An Account? Log in Now
Safety and Efficacy of Continuous Subcutaneous Levodopa–Carbidopa Infusion for Parkinson's Disease With Motor Fluctuations
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease.
METHODS
We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete.
FINDINGS
Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury).
INTERPRETATION
Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment.
Additional Info
Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial
Lancet Neurol 2024 Mar 15;[EPub Ahead of Print], AJ Espay, F Stocchi, R Pahwa, A Albanese, A Ellenbogen, JJ Ferreira, N Giladi, T Gurevich, S Hassin-Baer, J Hernandez-Vara, SH Isaacson, K Kieburtz, PA LeWitt, L Lopez-Manzanares, CW Olanow, W Poewe, H Sarva, T Yardeni, L Adar, L Salin, N Lopes, N Sasson, R Case, O RascolFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Continuous application of dopaminergics is believed to smooth fluctuations and reduce dyskinesia as a complication of treatment of Parkinson’s disease. Although other forms of continuous levodopa application already exist, including intrajejunal levodopa application, subcutaneous application of levodopa was eagerly awaited because it is the most established therapeutic principle and subcutaneous application is considered to be less risky than intrajejunal application. This study is clinically important and methodologically particularly well-conducted. Overall, 259 patients were randomized to subcutaneous administration of levodopa–carbidopa or oral administration. During a run-in phase of 12 weeks before randomization, all patients were characterized for their individually optimal dosage of both interventions. ON-time prolongation and OFF-time shortening are the main effects of the intervention, and these were improved to a clinically relevant degree, with an ON-time prolongation of 1.72 hours and an OFF-time reduction of 1.4 hours (minimal clinically relevant change, 1 hour).1 Regarding the activities of daily living measured with the MDS-UPDRS II, the improvements, as assessed by the patients and the physician, were also significantly in favor of the infusion therapy. As expected, there is little or no improvement in the motor ON state, because the drug effect is not different for oral and subcutaneous application, and the main advantage of the infusion therapy is the constant drug level in the blood. The time without disturbing dyskinesias (the best condition for the patient) was recorded; but, unfortunately, there is no information on the overall therapy complications recorded with the MDS-UPDRS IV. In any case, there were no increases in the rate of impulse control disorders, no relevant sleep disorders, and no daytime sleepiness. The very frequent dermatological complications appeared to be unavoidable with this therapy and led to discontinuation in 8% of the patients.
To date, there are two other comparable studies for Parkinson's disease therapeutics that apply dopaminergics subcutaneously (apomorphine2,3 and foslevodopa/foscarbidopa4). In addition, the intrajejunal pump application of levodopa–carbidopa is included in this therapeutic principle.5 These therapies are summarized as (invasive) infusion therapies,1 and their testing is methodologically complex because a dummy design has to be added and the placebo arm needs to have either oral or infusion therapy as placebo. All three therapies lead to an ON-time prolongation without dyskinesia of 1.7 to 2 hours, and the other secondary outcomes were similarly improved. There are only differences in quality of life, as apomorphine does not lead to an improvement, whereas this was found for both intrajejunal and subcutaneous levodopa administration.
This new therapy is an important addition to the therapeutic spectrum. The significant improvement in the control of fluctuations with acceptable and easily recognizable adverse effects are important for users. A clear preference for one or the other infusion therapy does not appear to be possible based on the convincing and high-quality studies to date.
References